PROJECT SUMMARY/ABSTRACT Cancer is a major health crisis with millions of new diagnoses each year. In response, researchers often turn to nature in search of molecules, often structurally sophisticated, which can serve as viable anticancer therapeutics. One such molecule is paclitaxel (Taxol), a highly oxygenated diterpenoid belonging to the taxoid family of natural products. While paclitaxel has proven to be an effective chemotherapeutic, its high lipophilicity and the emergence of resistant cancer cells pose many therapeutic challenges and create an urgency to study structurally distinct taxoids, such as taxagifine. Like paclitaxel, taxagifine and its congeners (collectively known as the oxo-bridged taxoids) possess significant anticancer properties but remain relatively underexplored both synthetically and biologically, especially with regard to their potential to overcome drug resistance. Given the urgency to address therapeutic challenges associated with paclitaxel, this proposal aims to establish the first synthetic approach to oxo-bridged taxoids from the feedstock chemical (S)-carvone, which will enable comprehensive biological evaluation of these molecules and provide insight into their potential to serve as alternative treatments to paclitaxel. These studies will be accomplished through three specific aims: 1) completing the total synthesis of taxagifine, 2) synthesizing additional oxo-bridged taxoids, including analogues, and 3) assessing their biological activity through collaborative efforts. The total synthesis of taxagifine and other oxo-bridged taxoids will be pursued through the execution of site- selective, late-stage functionalizations of a key intermediate, which is prepared convergently from two (S)- carvone-derived coupling partners using a C?C bond cleavage/cross-coupling strategy. Development of an efficient and robust synthetic route to taxagifine will set the stage for the synthesis of taxoid analogues, and ultimately, synthetic work proposed herein will enable not only the preparation of natural and unnatural taxoids, but will offer new strategies for the synthesis of other highly oxygenated terpenoids as well. Overall, synthetic and biological investigation of the oxo-bridged taxoids will provide significant insight into these underexplored molecules, opening the door to the next generation of potential anticancer therapeutics.